Drug Development from Natural Products Based on the Pathogenic Mechanism of Asthma

Asthma is a chronic inflammatory disease of the pulmonary system associated with many wheeze-to-sleep apnea complications that may lead to death. In 2019, approximately 262 million patients suffered from asthma, and 455 thousand died from the disease worldwide. It is a more severe health problem in children and older adults, and as the aging of society intensifies, the problem will continue to worsen. Asthma inducers can be classified as indoor and outdoor allergens and can cause asthma due to their repeated invasion. There are several theories about asthma occurrence, such as the imbalance between Th1 and Th2, inflammation in the pulmonary system, and the abnormal apoptosis/cell proliferation of cells related to asthma. Although there are many medications for asthma, as it is an incurable disease, the purpose of the drugs is only to suppress the symptoms. The current drugs can be divided into relievers and controllers; however, as they have many adverse effects, such as immune suppression, growth retardation, promotion of cataracts, hyperactivity, and convulsions, developing new asthma drugs is necessary. Although natural products can have adverse effects, the development of asthma drugs from natural products may be beneficial, as some have anti-asthmatic effects such as immune modulation, anti-inflammation, and/or apoptosis modulation.


Definition
Asthma is an incurable chronic inflammatory disease with a hyper-responsive reaction in the pulmonary system [1]. In particular, the Global Initiative for Asthma defines asthma as "a heterogeneous disease, usually characterized by chronic airway inflammation". It is defined by a history of respiratory symptoms, such as wheezing, shortness of breath, chest tightness, and cough. Various signs are observed according to the suffering time and intensity, as they are caused by variable expiratory airflow limitation [2]. Many patients simultaneously experience asthma, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnea. This coexistence can lead to patient death; therefore, an advanced therapeutic protocol should be developed [3].

Asthma Inducers
The major causes of asthma are complex factors that contribute to confuse the immune system in bio-organisms. There are many asthma inducers, such as allergens, pollutants, tobacco smoking, cold temperature, and genetic background [7]. Patients with non-allergic asthma (NA) may comprise 10-33% of the asthma cases. Intrinsic factors, such as genetic background, are the cause of NA; however, in the related study, only allergic asthma was described [8]. Although many allergens exist, they can be classified into two categories: indoor and outdoor. Indoor allergens include house dust mites (Der p 1 and Der p 2, from Dermatophagoides pteronyssinus), cockroaches (Bla g 1, Bla g 2, and Per a 1), pet dander (Fel d 1 from cat and Can f 1 from dog), and outdoor allergens include mice (Mus m 1), pollen (Phl p1 and Phl p5, from Timothy and Amb a 1, 2, 3, 5, and 6, from ragweed), peanut proteins (Ara h 1, 2, and 3), and mold (Alternaria, Cladosporium, and Epicoccum) [9,10]. Recently, the relationship between asthma occurrence and air pollutants, such as traffic-related air pollution, sulfur dioxide, carbon monoxide, heavy metals, and polycyclic aromatic hydrocarbons, has also been reported [11]. The prevalence and incidence of asthma in smokers are higher than in non-smokers, but the more severe aspect is non-smoker-related second-hand smoking, which is especially dangerous for children [12]. Cold weather can induce asthma symptoms that are more severe in patients with uncontrolled asthma than in those with well-controlled asthma [13]. Further, more than 100 genes have been shown to cause asthma, such as the BsmI (rs1544410) and ApaI (rs7975232) polymorphisms of the vitamin D receptor gene, the rs20541 and rs1800925 polymorphisms of IL13, and the rs4950928, rs10399931, and rs8883125 polymorphisms of chitinase 3-like 1 [14][15][16].

Histopathological Changes in Asthma Occurrence
Patients with asthma have problems ranging from wheezing to death due to apnea, and these problems are caused by obstacles to the pulmonary system. Airway remodeling, a representative change in the respiratory system, occurs from histopathological deformations such as respiratory epithelial cell hyperplasia, mucous hypersecretion by goblet cell hyperplasia, metaplasia, submucosal gland hypertrophy, inflammatory cell infiltration of eosinophils and neutrophils, and airway smooth muscle contraction [17][18][19][20].

Mechanisms of Asthma Pathogenesis
2.3.1. Imbalance of Th1, Th17, and Th2 The immune system is important in maintaining homeostasis in organisms, and its function can be classified into two categories: innate and acquired immunity [21]. In particular, acquired immunity is important in relation to a pathogen's reinvasion, as it has a memory of the pathogen's characteristics and can rapidly eliminate the reinvading pathogens. Although it is important to maintain the balance of helper T cell subfamilies such as Th1, Th2, and Th17 cells in bio-organisms, in diseases such as asthma, atopic dermatitis, and viral infection, the upregulation of Th2 cells is important and results in an imbalance of helper T cell subfamilies, leading to an imbalance of Th1, Th17, and Th2 cells [22]. In particular, Th17 cell abnormalities can induce neutrophilic asthma [20].
Regulatory T (Treg) cells are very important modulators of the balance between Th1 and Th2 cells, as they play a critical role in maintaining immune tolerance to allergens; however, when asthma occurs, the level of Treg cells changes ( Figure 1) [23]. Notably, Th2 cell-related cytokines such as IL-4, IL-5, and IL-13 and Th17 cell-related cytokines such as IL-6 and TNF-α increase in patients with asthma [24]. IL-4 stimulates the activation of GATA-3, which is a Th2 cell transcription factor, through a positive feedback loop, leading to the secretion of IgE by activating B cells, inducing eosinophilia, and stimulating airway hyperreactivity [25]. IL-5 activates B cells and increases the eosinophil population [26]. IL-13 causes goblet cell metaplasia, bronchial hyperreactivity, and eosinophil extravasation by stimulating the expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) [27]. IL-6 stimulates inflammation, promotes IL-4 production, and suppresses Th1 and Th17 cell differentiation, whereas TGF-β stimulates Th17 cell differentiation [22,28]. TNF-α is related to airway hyperresponsiveness [29]. In contrast to the increments of Th2 cell-and Th17 cell-related cytokines, the level of Th1 cell-related cytokines, such as IFN-γ and IL-12, decreases in patients with asthma [30]. IFN-γ has incompatible functions; it acts as a stimulator and activates Th1 cell transcription factor (T-bet), and as a suppressor, it activates Th2 cell transcription factor (GATA-3), preventing eosinophilia and inhibiting asthmatic changes such as airway hyperreactivity, inflammation, and mucous hypersecretion in the respiratory system [31,32]. IL-12 is related to Th1 cell differentiation and the suppression of Th2 cell propagation [33]. cell hyperplasia, metaplasia, submucosal gland hypertrophy, inflammatory cell infiltration of eosinophils and neutrophils, and airway smooth muscle contraction [17][18][19][20].

Mechanisms of Asthma Pathogenesis
2.3.1. Imbalance of Th1, Th17, and Th2 The immune system is important in maintaining homeostasis in organisms, and its function can be classified into two categories: innate and acquired immunity [21]. In particular, acquired immunity is important in relation to a pathogen's reinvasion, as it has a memory of the pathogen's characteristics and can rapidly eliminate the reinvading pathogens. Although it is important to maintain the balance of helper T cell subfamilies such as Th1, Th2, and Th17 cells in bio-organisms, in diseases such as asthma, atopic dermatitis, and viral infection, the upregulation of Th2 cells is important and results in an imbalance of helper T cell subfamilies, leading to an imbalance of Th1, Th17, and Th2 cells [22]. In particular, Th17 cell abnormalities can induce neutrophilic asthma [20].
Regulatory T (Treg) cells are very important modulators of the balance between Th1 and Th2 cells, as they play a critical role in maintaining immune tolerance to allergens; however, when asthma occurs, the level of Treg cells changes ( Figure 1) [23]. Notably, Th2 cell-related cytokines such as IL-4, IL-5, and IL-13 and Th17 cell-related cytokines such as IL-6 and TNF-α increase in patients with asthma [24]. IL-4 stimulates the activation of GATA-3, which is a Th2 cell transcription factor, through a positive feedback loop, leading to the secretion of IgE by activating B cells, inducing eosinophilia, and stimulating airway hyperreactivity [25]. IL-5 activates B cells and increases the eosinophil population [26]. IL-13 causes goblet cell metaplasia, bronchial hyperreactivity, and eosinophil extravasation by stimulating the expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) [27]. IL-6 stimulates inflammation, promotes IL-4 production, and suppresses Th1 and Th17 cell differentiation, whereas TGF-β stimulates Th17 cell differentiation [22,28]. TNF-α is related to airway hyperresponsiveness [29]. In contrast to the increments of Th2 cell-and Th17 cell-related cytokines, the level of Th1 cellrelated cytokines, such as IFN-γ and IL-12, decreases in patients with asthma [30]. IFN-γ has incompatible functions; it acts as a stimulator and activates Th1 cell transcription factor (T-bet), and as a suppressor, it activates Th2 cell transcription factor (GATA-3), preventing eosinophilia and inhibiting asthmatic changes such as airway hyperreactivity, inflammation, and mucous hypersecretion in the respiratory system [31,32]. IL-12 is related to Th1 cell differentiation and the suppression of Th2 cell propagation [33]. In healthy conditions, the balance of Th1, Th17, and Th2 cells can be maintained, but asthma inducers stimulate their imbalance. Treg cells modulate the immune balance between Th1, Th17, and Th2 cells, as they can regulate the development of naïve T cells to Th1, Th17, or Th2 cells. Th1, helper 1 T cell; Th2, helper 2 T cell; Th17, helper 17 T cell; Treg, regulatory T cell. In healthy conditions, the balance of Th1, Th17, and Th2 cells can be maintained, but asthma inducers stimulate their imbalance. Treg cells modulate the immune balance between Th1, Th17, and Th2 cells, as they can regulate the development of naïve T cells to Th1, Th17, or Th2 cells. Th1, helper 1 T cell; Th2, helper 2 T cell; Th17, helper 17 T cell; Treg, regulatory T cell.

Inflammation in the Pulmonary System
Asthma is a heterogeneous inflammatory disease, and various inducers cause the infiltration of immune cells, such as eosinophils and neutrophils, which release reactive oxygen species (ROS) to eliminate them. After the elimination of foreign bodies, the redox According to the development time, respiratory inflammation-related asthma can be classified into two categories, i.e., acute and chronic, with acute asthma presenting an early a late phase (Table 1) [35]. The early phase of the acute inflammation stage occurs within several minutes of allergen exposure due to the cross-linking of allergens with IgE, which binds to immune cells such as mast cells and basophils. The cross-linked allergens can then release immune mediators such as cytokines and chemokines to affect the functions of several organs, including vasodilation, vascular permeability, bronchoconstriction, and mucus hypersecretion. The late phase occurs within 2-6 h after allergen invasion; the peak occurs 6-9 h later, and several symptoms can be observed, such as wheezing, shortness of breath, and cough. These symptoms are caused by an increase in Th2 cell-related cytokines, such as IL-4, IL-5, and IL-13, via Th2 cell activation and an increase in white blood cell populations, such as eosinophils, basophils, and other leukocytes. The chronic inflammation stage of the respiratory system is caused by repeated allergen contact, which can change organ function via a continuous alteration of the extracellular matrix and constitutive cells, ultimately inducing asthma.  Asthma is a heterogeneous inflammatory disease, and various inducers cause the infiltration of immune cells, such as eosinophils and neutrophils, which release reactive oxygen species (ROS) to eliminate them. After the elimination of foreign bodies, the redox imbalance maintains ROS overproduction, inducing oxidative stress in the respiratory system. This stress, including inflammation, damages the respiratory system and induces hyperresponsiveness, airway remodeling, and mucus hypersecretion ( Figure 2) [34]. According to the development time, respiratory inflammation-related asthma can be classified into two categories, i.e., acute and chronic, with acute asthma presenting an early a late phase (Table 1) [35]. The early phase of the acute inflammation stage occurs within several minutes of allergen exposure due to the cross-linking of allergens with IgE, which binds to immune cells such as mast cells and basophils. The cross-linked allergens can then release immune mediators such as cytokines and chemokines to affect the functions of several organs, including vasodilation, vascular permeability, bronchoconstriction, and mucus hypersecretion. The late phase occurs within 2-6 h after allergen invasion; the peak occurs 6-9 h later, and several symptoms can be observed, such as wheezing, shortness of breath, and cough. These symptoms are caused by an increase in Th2 cell-related cytokines, such as IL-4, IL-5, and IL-13, via Th2 cell activation and an increase in white blood cell populations, such as eosinophils, basophils, and other leukocytes. The chronic inflammation stage of the respiratory system is caused by repeated allergen contact, which can change organ function via a continuous alteration of the extracellular matrix and constitutive cells, ultimately inducing asthma. Asthma is a heterogeneous inflammatory disease, and various inducers cause the infiltration of immune cells, such as eosinophils and neutrophils, which release reactive oxygen species (ROS) to eliminate them. After the elimination of foreign bodies, the redox imbalance maintains ROS overproduction, inducing oxidative stress in the respiratory system. This stress, including inflammation, damages the respiratory system and induces hyperresponsiveness, airway remodeling, and mucus hypersecretion ( Figure 2) [34]. According to the development time, respiratory inflammation-related asthma can be classified into two categories, i.e., acute and chronic, with acute asthma presenting an early a late phase (Table 1) [35]. The early phase of the acute inflammation stage occurs within several minutes of allergen exposure due to the cross-linking of allergens with IgE, which binds to immune cells such as mast cells and basophils. The cross-linked allergens can then release immune mediators such as cytokines and chemokines to affect the functions of several organs, including vasodilation, vascular permeability, bronchoconstriction, and mucus hypersecretion. The late phase occurs within 2-6 h after allergen invasion; the peak occurs 6-9 h later, and several symptoms can be observed, such as wheezing, shortness of breath, and cough. These symptoms are caused by an increase in Th2 cell-related cytokines, such as IL-4, IL-5, and IL-13, via Th2 cell activation and an increase in white blood cell populations, such as eosinophils, basophils, and other leukocytes. The chronic inflammation stage of the respiratory system is caused by repeated allergen contact, which can change organ function via a continuous alteration of the extracellular matrix and constitutive cells, ultimately inducing asthma. Asthma is a heterogeneous inflammatory disease, and various inducers cause the infiltration of immune cells, such as eosinophils and neutrophils, which release reactive oxygen species (ROS) to eliminate them. After the elimination of foreign bodies, the redox imbalance maintains ROS overproduction, inducing oxidative stress in the respiratory system. This stress, including inflammation, damages the respiratory system and induces hyperresponsiveness, airway remodeling, and mucus hypersecretion ( Figure 2) [34]. According to the development time, respiratory inflammation-related asthma can be classified into two categories, i.e., acute and chronic, with acute asthma presenting an early a late phase (Table 1) [35]. The early phase of the acute inflammation stage occurs within several minutes of allergen exposure due to the cross-linking of allergens with IgE, which binds to immune cells such as mast cells and basophils. The cross-linked allergens can then release immune mediators such as cytokines and chemokines to affect the functions of several organs, including vasodilation, vascular permeability, bronchoconstriction, and mucus hypersecretion. The late phase occurs within 2-6 h after allergen invasion; the peak occurs 6-9 h later, and several symptoms can be observed, such as wheezing, shortness of breath, and cough. These symptoms are caused by an increase in Th2 cell-related cytokines, such as IL-4, IL-5, and IL-13, via Th2 cell activation and an increase in white blood cell populations, such as eosinophils, basophils, and other leukocytes. The chronic inflammation stage of the respiratory system is caused by repeated allergen contact, which can change organ function via a continuous alteration of the extracellular matrix and constitutive cells, ultimately inducing asthma. Asthma is a heterogeneou infiltration of immune cells, suc oxygen species (ROS) to elimina imbalance maintains ROS over system. This stress, including in hyperresponsiveness, airway rem According to the developm classified into two categories, i early a late phase (Table 1) [35]. within several minutes of allerge which binds to immune cells su can then release immune med functions of several organ bronchoconstriction, and mucus allergen invasion; the peak occu such as wheezing, shortness of increase in Th2 cell-related cytok and an increase in white blood c leukocytes. The chronic inflam repeated allergen contact, which the extracellular matrix and con Asthma is a heterogeneous inflammatory disease, and various inducers cause the infiltration of immune cells, such as eosinophils and neutrophils, which release reactive oxygen species (ROS) to eliminate them. After the elimination of foreign bodies, the redox imbalance maintains ROS overproduction, inducing oxidative stress in the respiratory system. This stress, including inflammation, damages the respiratory system and induces hyperresponsiveness, airway remodeling, and mucus hypersecretion (Figure 2) [34]. According to the development time, respiratory inflammation-related asthma can be classified into two categories, i.e., acute and chronic, with acute asthma presenting an early a late phase (Table 1) [35]. The early phase of the acute inflammation stage occurs within several minutes of allergen exposure due to the cross-linking of allergens with IgE, which binds to immune cells such as mast cells and basophils. The cross-linked allergens can then release immune mediators such as cytokines and chemokines to affect the functions of several organs, including vasodilation, vascular permeability, bronchoconstriction, and mucus hypersecretion. The late phase occurs within 2-6 h after allergen invasion; the peak occurs 6-9 h later, and several symptoms can be observed, such as wheezing, shortness of breath, and cough. These symptoms are caused by an increase in Th2 cell-related cytokines, such as IL-4, IL-5, and IL-13, via Th2 cell activation and an increase in white blood cell populations, such as eosinophils, basophils, and other leukocytes. The chronic inflammation stage of the respiratory system is caused by repeated allergen contact, which can change organ function via a continuous alteration of the extracellular matrix and constitutive cells, ultimately inducing asthma. According to the development time, respiratory inflammation-related asthma can be classified into two categories, i.e., acute and chronic, with acute asthma presenting an early a late phase (Table 1) [35]. The early phase of the acute inflammation stage occurs within several minutes of allergen exposure due to the cross-linking of allergens with IgE, which binds to immune cells such as mast cells and basophils. The cross-linked allergens can then release immune mediators such as cytokines and chemokines to affect the functions of several organs, including vasodilation, vascular permeability, bronchoconstriction, and mucus hypersecretion. The late phase occurs within 2-6 h after allergen invasion; the peak occurs 6-9 h later, and several symptoms can be observed, such as wheezing, shortness of breath, and cough. These symptoms are caused by an increase in Th2 cell-related cytokines, such as IL-4, IL-5, and IL-13, via Th2 cell activation and an increase in white blood cell populations, such as eosinophils, basophils, and other leukocytes. The chronic inflammation stage of the respiratory system is caused by repeated allergen contact, which can change organ function via a continuous alteration of the extracellular matrix and constitutive cells, ultimately inducing asthma. Toll-like receptors (TLRs) play an important role in innate and acquired immunity, and TLR cascades in the respiratory system are closely associated with asthma and COPD [36]. The commensal microbiota in the gastrointestinal tract controls innate and acquired immune responses and is related to the immune reaction at extraintestinal sites, such as in the respiratory system. However, the immune response of the commensal microbiota in the respiratory system is not caused by TLRs on pulmonary cells but is related to bacterial Nod-like receptors (NLRs) in the digestive system [37]. This indicates that the NLR on the microbiota binds to NLR ligands and induces alveolar macrophages to release oxygen species to kill invading bacteria.

Apoptosis/Cell Proliferation of Respiratory Epithelial Cells
The epithelial cell layer is the most important barrier against foreign bodies and invading bio-organisms, and foreign bodies, including asthma inducers, can damage this area through inflammation [38]. Owing to their role as a barrier, the repeated damage and recovery of pulmonary epithelial cells results in their apoptosis, and new cells emerge to replace the functions of dead cells [39]. However, reports regarding the relationship between apoptosis and asthma are contradictory. Some studies showed that epithelial cell apoptosis is a representative change related to asthma occurrence [40,41]. However, other researchers found that the population of apoptotic cells significantly increases in patients with steroid-untreated asthma [42,43]. These contradictory results might be depend on the epithelial cell stage in relation to the elimination of damaged/dying cells, which is induced by various stimulators, as the neighboring epithelial cells of damaged/dying cells may engulf the apoptotic cells [44].
Apoptosis is a homeostatic process that is related to normal cell turnover, immune system development and function, hormone release, and embryonic development [45]. Its mechanism is classified into three types, i.e., intrinsic (mitochondrial), extrinsic (death receptor), and related to perforin/5ranzyme (Figure 3) [46], which are connected to the execution pathway. The intrinsic pathway is not related to the receptor and is initiated by increased mitochondrial permeability; its initiator is caspase-8 [47], and the Bcl-2 family of proteins, which controls mitochondrial permeability, is strongly involved in this pathway [48]. The Bcl-2 family of proteins can be divided into two categories: anti-apoptotic proteins, including Bcl-2, Bcl-x, Bcl-XL, Bcl-XS, Bcl-w, and BAG, and pro-apoptotic proteins, including Bcl-10, Bax, Bak, Bid, Bad, Bim, Bik, and Blk [45]. extrinsic pathway requires apoptosis-related receptors and ligand binding, and the initiator is caspase-8. The perforin/granzyme pathway is activated by perforin and granzymes A/B activation. The second step is the execution pathway, in which representative changes related to apoptosis are observed [45][46][47][48][49][50][51][52][53][54][55][56]. Figure 3. Mechanisms of apoptosis. The intrinsic pathway is related to mitochondrial activity, the extrinsic pathway is initiated by the binding of an apoptotic ligand to the apoptotic receptor, and the perforin/granzyme pathway is related to perforin and granzyme. Cell death (apoptosis) is completed through the execution pathway, which leads to chromatin condensation, membrane blebbing, and nuclear collapse. , apoptotic ligand; , apoptotic receptor; , perforin; , granzyme.
Although the relationship between apoptosis and proliferation is controversial, it is strongly related to cellular homeostasis, as it can block cellular proliferation and promote apoptotic events. The inhibition of pulmonary epithelial cell proliferation in patients with asthma might be similar to that observed in steroid-treated patients, in which the number of apoptotic cells increases [42,43]. The NF-κB/COX-2 pathway is related to both cell proliferation and inflammation, and NF-κB, as a transcription factor, induces the expression of COX-2. Finally, this pathway suppresses apoptosis when the number of tumor cells Figure 3. Mechanisms of apoptosis. The intrinsic pathway is related to mitochondrial activity, the extrinsic pathway is initiated by the binding of an apoptotic ligand to the apoptotic receptor, and the perforin/granzyme pathway is related to perforin and granzyme. Cell death (apoptosis) is completed through the execution pathway, which leads to chromatin condensation, membrane blebbing, and nuclear collapse.

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Asthma is a heterogeneous inflammatory disease, and various inducers cause the infiltration of immune cells, such as eosinophils and neutrophils, which release reactive oxygen species (ROS) to eliminate them. After the elimination of foreign bodies, the redox imbalance maintains ROS overproduction, inducing oxidative stress in the respiratory system. This stress, including inflammation, damages the respiratory system and induces hyperresponsiveness, airway remodeling, and mucus hypersecretion (Figure 2) [34]. According to the development time, respiratory inflammation-related asthma can be classified into two categories, i.e., acute and chronic, with acute asthma presenting an early a late phase ( The apoptotic pathway is summarized as follows. The apoptotic pathway consists of two steps; the first step can be divided into three categories: intrinsic, extrinsic, and perforin/granzyme pathways. The intrinsic pathway is not related to transmembrane receptors but is strongly related to mitochondrial changes, and the initiator is caspase-3. The extrinsic pathway requires apoptosis-related receptors and ligand binding, and the initiator is caspase-8. The perforin/granzyme pathway is activated by perforin and granzymes A/B activation. The second step is the execution pathway, in which representative changes related to apoptosis are observed [45,46,47,48,49,50,51,52,53,54,55,56]. Figure 3. Mechanisms of apoptosis. The intrinsic pathway is related to mitochondrial activity, the extrinsic pathway is initiated by the binding of an apoptotic ligand to the apoptotic receptor, and the perforin/granzyme pathway is related to perforin and granzyme. Cell death (apoptosis) is completed through the execution pathway, which leads to chromatin condensation, membrane blebbing, and nuclear collapse.
Although the relationship between apoptosis and proliferation is controversial, it is strongly related to cellular homeostasis, as it can block cellular proliferation and promote apoptotic events. The inhibition of pulmonary epithelial cell proliferation in patients with The apoptotic pathway is summarized as follows. The apoptotic pathway consists of two steps; the first step can be divided into three categories: intrinsic, extrinsic, and perforin/granzyme pathways. The intrinsic pathway is not related to transmembrane receptors but is strongly related to mitochondrial changes, and the initiator is caspase-3. The extrinsic pathway requires apoptosis-related receptors and ligand binding, and the initiator is caspase-8. The perforin/granzyme pathway is activated by perforin and granzymes A/B activation. The second step is the execution pathway, in which representative changes related to apoptosis are observed [45,46,47,48,49,50,51,52,53,54,55,56]. Figure 3. Mechanisms of apoptosis. The intrinsic pathway is related to mitochondrial activity, the extrinsic pathway is initiated by the binding of an apoptotic ligand to the apoptotic receptor, and the perforin/granzyme pathway is related to perforin and granzyme. Cell death (apoptosis) is completed through the execution pathway, which leads to chromatin condensation, membrane blebbing, and nuclear collapse.
Although the relationship between apoptosis and proliferation is controversial, it is strongly related to cellular homeostasis, as it can block cellular proliferation and promote apoptotic events. The inhibition of pulmonary epithelial cell proliferation in patients with The apoptotic pathway is summarized as follows. The apoptotic pathway consists of two steps; the first step can be divided into three categories: intrinsic, extrinsic, and perforin/granzyme pathways. The intrinsic pathway is not related to transmembrane receptors but is strongly related to mitochondrial changes, and the initiator is caspase-3. The extrinsic pathway requires apoptosis-related receptors and ligand binding, and the initiator is caspase-8. The perforin/granzyme pathway is activated by perforin and granzymes A/B activation. The second step is the execution pathway, in which representative changes related to apoptosis are observed [45,46,47,48,49,50,51,52,53,54,55,56]. Figure 3. Mechanisms of apoptosis. The intrinsic pathway is related to mitochondrial activity, the extrinsic pathway is initiated by the binding of an apoptotic ligand to the apoptotic receptor, and the perforin/granzyme pathway is related to perforin and granzyme. Cell death (apoptosis) is completed through the execution pathway, which leads to chromatin condensation, membrane blebbing, and nuclear collapse.
Although the relationship between apoptosis and proliferation is controversial, it is strongly related to cellular homeostasis, as it can block cellular proliferation and promote apoptotic events. The inhibition of pulmonary epithelial cell proliferation in patients with , granzyme.
The apoptotic pathway is summarized as follows. The apoptotic pathway consists of two steps; the first step can be divided into three categories: intrinsic, extrinsic, and perforin/granzyme pathways. The intrinsic pathway is not related to transmembrane receptors but is strongly related to mitochondrial changes, and the initiator is caspase-3. The extrinsic pathway requires apoptosis-related receptors and ligand binding, and the initiator is caspase-8. The perforin/granzyme pathway is activated by perforin and granzymes A/B activation. The second step is the execution pathway, in which representative changes related to apoptosis are observed [45][46][47][48][49][50][51][52][53][54][55][56].
Although the relationship between apoptosis and proliferation is controversial, it is strongly related to cellular homeostasis, as it can block cellular proliferation and promote apoptotic events. The inhibition of pulmonary epithelial cell proliferation in patients with asthma might be similar to that observed in steroid-treated patients, in which the number of apoptotic cells increases [42,43]. The NF-κB/COX-2 pathway is related to both cell proliferation and inflammation, and NF-κB, as a transcription factor, induces the expression of COX-2. Finally, this pathway suppresses apoptosis when the number of tumor cells increases [57] and increases inflammation in patients with asthma [58]. Based on these studies, the search for inhibitors of the NF-κB/COX-2 pathway is one of the strategies to develop asthma drug candidates.
The pathogenesis of asthma can be attributed to various inducers and can be established by an imbalance between Th1 and Th2 cells, inflammation in the pulmonary system, and anti-apoptosis/cell proliferation of respiratory epithelial cells.
The use of methylxanthines has gradually decreased because of their side effects. However, some methylxanthines, such as theophylline, are recommended as anti-asthmatic drugs because they have bronchodilatory and anti-inflammatory effects [63,64]. Inflammation begins with cell membrane destruction and ends with the production of leukotrienes or prostaglandins. Corticosteroids block the conversion of phospholipase A 2 from the plasma membrane to arachidonic acid and can completely prevent inflammation. Inhalable corticosteroids are mainly used as anti-asthmatic agents [65,66]. Leukotrienes (LTs), which can be classified as cysteinyl-TLs (LTC 4 , LTD 4 , and LTE 4 ) and LTB 4 , are pivotal for the occurrence of asthma. Cysteinyl-TLs induce airway remodeling and asthma exacerbation via inflammation [67,68]. The allergic response by mast cells is initiated by the interaction of the allergen with the IgE-FcεRI complex and maintained by chemical mediators such as histamine released by mast cells [69]. Mast cell stabilizers inhibit their activation and decrease asthma exacerbation [70].

Adverse Effects of the Current Drugs
Xie et al. reported that, in the USA from 2000 to 2016, 12,640 of 698,501 patients with asthma from 0 to 20 years of age (1.7%) experienced adverse effects of asthma drugs, and 0.83% of the adverse events were related to corticosteroids [71]. In particular, in patients aged 0-4 years, the incidence rate of asthma drugs' adverse effects significantly increased from 0.2% to 19.3%. In the early stages of bronchodilator use, excessive doses of compounds such as isoprenaline cause toxicity in users [72]. The side effects of anticholinergics include a dry mouth, constipation, cough, headaches, and nausea; those of β 2 -adrenergic receptor agonists include trembling, nervous tension, headaches, muscle cramps, and heart attack; theophylline, a methylxanthine, causes nausea/vomiting, diarrhea, palpitation, tachycardia, arrhythmia, headaches, and insomnia [73]. The adverse effects of corticosteroids include cataract/glaucoma in the eye, hypertension/hyperlipidemia in the cardiovascular system, peptic ulcer/pancreatitis in the gastrointestinal tract, myopathy/osteoporosis in the skeletal muscle, dermal atrophy in the skin, immunological suppression, and growth retardation, especially in children [74,75]. The adverse effects of leukotriene modifiers are more common in children than in adults and are classified into psychiatric and non-psychiatric types. The psychiatric effects include hyperactivity, excessive sleepiness, nyctophobia, nervousness, agitation, hallucinations, and sleep disorders. The nonpsychiatric effects include abdominal pain, rash, aphthous ulcers, increased appetite, headache, and convulsions [76]. Mast cell stabilizers have several adverse effects, such as throat irritation, cough, anaphylaxis, and headache [77,78]. Immune modulators can help control asthma symptoms including nausea, increased serum aminotransferase, diarrhea, and hair problems [79].
The current drugs for asthma treatment are used only for preventing/relieving asthma symptoms, not for curing the disease, and they have many adverse effects; therefore, the development of new drugs is necessary.

Natural Drugs for Asthma Treatment
As the current asthma drugs have many adverse effects, natural drug development might be an advisable method. In this section, studies on natural asthma drug development are classified according to the mechanism of asthma occurrence (Table 3).

Immune Modulators
Chrysin, which is 5,7-dihydroxyflavone and originates from propolis and passion flowers, controls asthmatic changes in a murine model by decreasing the levels of IgE, IL-4, and IL-13 [80]. 1 -Acetoxychavicol acetate isolated from Alpinia galanga, which is used as a traditional drug for gastric ulceritis, inhibits the release of Th2 cell-related cytokines, such as IL-4, IL-5, and IL-13, and Th1 cell-related cytokines, such as IL-12 and IFN-γ [81]. Alginate oligosaccharide, fermented by Bacillus subtilis KCTC 11782BP, inhibits the release of IL-5 and IL-13 [82]. Allium cepa L., which has long been used as an anti-inflammatory drug, downregulates Blomia tropicalis-induced Th2 cell-related cytokines, such as IL-4 and IL-13 [83]. Allium hookeri, which is used as a culinary material, significantly inhibits the release of Th2 cell-related cytokines, such as IL-4, IL-5, and IL-13 [84]. Anoectochilus formosanus HAYATA, a traditional drug, suppressed IgE, IL-4, and IL-5 levels in an asthma model [85]. Caenorhabditis elegans extracts decreased IgE, IL-5, and IL-13 and increased IFN-γ levels [86]. Camellia japonica oil, which is used as a hair cosmetic, controls ovalbumininduced asthma via the GATA-3 and IL-4 pathways, and the active compound is oleic acid [87]. Citrus tachibana, a fruit, restored the balance of Th1/Th2 via the downregulation of Th2 cell-related cytokines such as IL-4 and IL-5 and the upregulation of Th1 cell-related cytokines such as IL-12 and IFN-γ, the imbalance of which was induced by ovalbumin [88]. Curcumin from Curcuma longa, which has long been used as an anti-inflammatory drug, significantly decreased asthmatic changes in the pulmonary system by downregulating the levels of GATA-3, a Th2 cell transcription factor [89]. Erythronium japonicum, a culinary material, suppressed Th1-related cytokines, such as IL-12p35 and IFN-γ, and Th2-related cytokines, such as IL-4, IL-5, and IL-13 [90]. Korean red ginseng exerted anti-asthmatic effects by modulating IL-12, IL-4, and IL-6 [91], and Mycoleptodonoides aitchisonii, a culinary material, significantly downregulated the levels of IL-4, IL-5, and IL-13 [92]. Opuntia humifusa, a culinary ingredient, suppressed ovalbumin-induced asthmatic changes by regulating Th1-/Th2-/Th17-related cytokines [93]. Table 3. Anti-asthmatic effects of natural products based on the therapeutic pathway. The source indicates the origin of the applied material. The applied type is the treatment form described in this study: if the applied form is the isolated compound, it is described as "Isolated compound/active substance". However, if the active substance is known but is different from the applied form, they are indicated as "applied type and active substance". P.O., oral administration; Refs., references.

Anti-Inflammatory Effectors
Chrysin exerts an immunomodulatory and anti-inflammatory effects by downregulating Th2 cell-related cytokines and blocking inflammatory cell infiltration in the pulmonary system, respectively [80]. Three methoxy-catalpoides from Psueolysimachion rotundum var. subintegrum suppressed inflammation by decreasing the expression of COX-2 and iNOS and downregulating the levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α [94]. Aster yomensa (Kitam). Honda, a culinary material, ameliorated inflammation through the downregulation of NO and IL-1β, which are related to TLR4 and NF-κB actions [95]. Codonopsis laceolata, which is used as a drug and as culinary material, suppressed asthma severity through NF-κB/COX-2 and PEG 2 pathways [96]. Echinodorus scaber rataj controls inflammation by downregulating inflammatory cell migration [97]. Korean red ginseng suppressed asthma occurrence through the dual effects of immune modulation via IL-4 downregulation and inflammation inhibition through the NF-κB/COX-2 and PEG 2 pathways [91]. Pericampylus glaucus inhibited inflammation by blocking the synthesis of COX-1 and COX-2 [98]. Pinus maritime decreased inflammation by enhancing the HO-1 antioxidative system and suppressing the levels of proinflammatory cytokines such as IL-1β and IL-6 [99]. Saururus chinensis, a culinary material, inhibited inflammation by blocking NF-κB activation and the expression of COX-2 and PEG 2 [100].

Apoptosis Modulators
Chrysin exerts anti-asthmatic effects via several therapeutic pathways, such as immune modulation, anti-inflammation, and apoptosis induction. Further, it induced the apoptosis of airway smooth muscle cells through the dephosphorylation of ERK1/2 [101]. Codonopsis laceolata significantly controls ovalbumin-induced inflammation and cell death, such as apoptosis of infiltrated inflammatory cells and pulmonary epithelial cell death [96]. Curcumin induces cell death by decreasing the expression of the anti-apoptotic protein Bcl-2 and induces endoplasmic reticulum stress [102].
The safety of natural products has been well demonstrated, as they have been used for a long time, and it is easy to develop new drugs for asthma treatment using them because of their anti-asthmatic effects. As drug development is based on the pathogenesis of the disease, natural products are classified into three categories by studies on their anti-asthmatic properties: immune modulators, anti-inflammatory effectors, and apoptosis modulators.

Discussion
According to a WHO Fact Sheet of 2019, 262 million people suffered from asthma and 455 thousand persons died from the disease. Asthma is a severe health problem for children and older adults [4], and as the aging of society intensifies [5], it is likely that the population of patients with asthma will increase. Although allergic asthma inducers involve indoor and outdoor allergens, air pollution and climate change have been intensively considered as additional severe factors that accelerate the prevalence of asthma owing to the rapid industrialization [11,103].
Asthma medications consist of a controller and a reliever [60]. The controller blocks inflammation or modulates the immune reaction [59], and the reliever controls asthma by dilating the pulmonary smooth muscle to expand the small airways [62].
When the allergen invades a bio-organism repeatedly, the immune system is activated, resulting in the activation of immune cells, such as eosinophils and neutrophils, which in turn eliminate the allergens by producing ROS. Although the synthesized ROS may eliminate allergens, they can harm the bio-organism. Finally, repeated immune cell activation causes damage to the pulmonary system, including inflammation and airway remodeling, and can cause chronic asthma [34]. Potent anti-inflammatory drugs, such as corticosteroids, leukotriene modifiers, and mast cell stabilizers, have long been used but have several adverse effects [75][76][77][78].
The levels of Th2 cell-related factors are significantly increased in patients with asthma [22], and Th2 cell-related cytokines, such as IL-4, IL-5, and IL-13, have many functions related to asthma occurrence, such as stimulating the secretion of IgE by activating B cells, inducing eosinophilia and airway hyper-responsiveness, and stimulating goblet cell metaplasia [25][26][27]. Other asthma controllers include immune modulators such as immune suppressors (methotrexate and cyclosporine A) and immune potentiators (glucocorticoids, 1,25-dihydroxy vitamin D3, and toll-like receptor 2/4/9 ligands). However, they have several adverse effects, such as nausea, an increase in serum aminotransferase, diarrhea, and hair problems [59,79]. A combined therapy with a reliever and controller is usually used to increase the anti-asthmatic effect of a drug and decrease its adverse effects [60]. Many studies have been conducted to develop safer and more effective drugs for asthma, including the investigation of natural products with anti-asthmatic effects. However, although natural products have long been used, they have not been confirmed to be safer than chemical drugs. For example, Guryanova et al. [104] reported that natural products, including those from bacterial sources, have dual effects depending on the time of administration. If they are used before the onset of asthma, which can be referred to as sensitization in an experimental model system, the severity of asthma can be significantly reduced; however, if used after the disease is established, they increase asthma severity. Therefore, the timing of administering natural products, including those from bacterial sources, to treat asthma is one of the most important factors to consider.
To develop asthma drugs from natural products, we should restrict the range of candidates that have long been used but lack reports on toxicity. Consequently, their toxicity should be evaluated before approval for market entry. In conclusion, natural products have many biological effects and can be used as drugs for asthma to exert immune modulation, anti-inflammation, and apoptosis modulation. Therefore, the development of drugs from natural products for the treatment of asthma may be a useful strategy.

Conflicts of Interest:
The authors declare no conflict of interest.